Tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia, are degenerative disorders characterized by accumulation of aggregated tau protein in the brains of affected individuals. AD affects an estimated 5.2 million Americans, and is the only cause of death among the top ten in the US that lacks a disease-modifying therapy or method of prevention. It has become increasingly recognized that tau-based therapies may be effective in treating AD, with the added benefit of potentially being used to treat other tauopathies. Unfortunately, major gaps in our understanding of tau-induced neurodegeneration remain a barrier to therapeutic intervention. Using a simple genetic model of tauopathy in Drosophila melanogaster that recapitulates many key features of these diseases, as well as tau transgenic mice and human AD brain tissue, we have identified heterochromatin loss as a mechanism of tau-induced neurodegeneration. The overall goal of the proposed project is to determine the upstream mediators and downstream consequences of heterochromatin loss in tauopathies. The K99 phase of this award will be conducted at Brigham and Women's Hospital and Harvard Medical School under the mentorship of Dr. Mel Feany and co-mentorship of Dr. David Pellman, where super-resolution microscopy, cell biological, biochemical, and genetic approaches will be used to identify the mechanisms leading to heterochromatin loss in tauopathies (Aim I). In the independent phase of this award, small RNA sequencing and other biochemical and genetic approaches will be used to identify the consequences of tau-induced heterochromatin loss (Aim II). The combination of classical and highly innovative techniques with novel hypotheses and targets in a well described model of tauopathy will lead to key advances in our understanding of tau-induced neurodegeneration and the development of disease-modifying therapies. Formal and informal interactions between Dr. Frost and her mentors, Drs. Feany and Pellman, will provide training and career guidance throughout this award. During the mentored phase of this award, Dr. Frost will gain professional skills that are vital to her long-term success as an academic through courses offered through Brigham and Womens Office of Research Careers and Harvard Catalyst. The proposed studies and career development plan are central to her scientific growth and advancement to independent investigator.